title: 1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists.
abstract: The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: L
authors.initials: L
authors.lastname: Merritt
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: C H
authors.initials: CH
authors.lastname: Mitch
authors.forename: C
authors.initials: C
authors.lastname: Whitesitt
authors.forename: D
authors.initials: D
authors.lastname: Brunsting
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: P H
authors.initials: PH
authors.lastname: Olesen
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: L
authors.initials: L
authors.lastname: Jeppesen
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011812:Quinuclidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D055672:Static Electricity; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D011812:Quinuclidines; D013830:Thiadiazoles; C084650:aceclidine